EP0909559A2 - Die Verwendung eines Na+/H+-Austauschers zur Herstellung eines Medikaments zur Behandlung oder Propphylaxe von Erkrankungen des Zentralnervensystems - Google Patents
Die Verwendung eines Na+/H+-Austauschers zur Herstellung eines Medikaments zur Behandlung oder Propphylaxe von Erkrankungen des Zentralnervensystems Download PDFInfo
- Publication number
- EP0909559A2 EP0909559A2 EP98117765A EP98117765A EP0909559A2 EP 0909559 A2 EP0909559 A2 EP 0909559A2 EP 98117765 A EP98117765 A EP 98117765A EP 98117765 A EP98117765 A EP 98117765A EP 0909559 A2 EP0909559 A2 EP 0909559A2
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- European Patent Office
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 21
- 238000011282 treatment Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 210000003169 central nervous system Anatomy 0.000 title claims description 10
- 238000011321 prophylaxis Methods 0.000 title claims description 6
- 201000010099 disease Diseases 0.000 title claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 5
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical group [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 title 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 540
- 239000000460 chlorine Substances 0.000 claims description 533
- 229910052801 chlorine Inorganic materials 0.000 claims description 523
- 229910052731 fluorine Inorganic materials 0.000 claims description 497
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 481
- 229910052739 hydrogen Inorganic materials 0.000 claims description 409
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 372
- 239000001257 hydrogen Substances 0.000 claims description 358
- 125000004432 carbon atom Chemical group C* 0.000 claims description 343
- 125000000217 alkyl group Chemical group 0.000 claims description 338
- -1 chloro, methyl Chemical group 0.000 claims description 318
- 229910052760 oxygen Inorganic materials 0.000 claims description 309
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 294
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 278
- 125000001424 substituent group Chemical group 0.000 claims description 274
- 239000001301 oxygen Substances 0.000 claims description 265
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 224
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 156
- 229910052794 bromium Inorganic materials 0.000 claims description 155
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 148
- 229910052717 sulfur Inorganic materials 0.000 claims description 146
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 141
- 229910052740 iodine Inorganic materials 0.000 claims description 132
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 111
- 125000001624 naphthyl group Chemical group 0.000 claims description 93
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 84
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 78
- 229910052799 carbon Inorganic materials 0.000 claims description 67
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 claims description 62
- 125000003342 alkenyl group Chemical group 0.000 claims description 57
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 49
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical group 0.000 claims description 23
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000002883 imidazolyl group Chemical group 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 17
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 14
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 14
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 12
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000001589 carboacyl group Chemical group 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 230000000302 ischemic effect Effects 0.000 claims description 8
- 210000002569 neuron Anatomy 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 206010001497 Agitation Diseases 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
- IWXNYAIICFKCTM-UHFFFAOYSA-N cariporide Chemical compound CC(C)C1=CC=C(C(=O)N=C(N)N)C=C1S(C)(=O)=O IWXNYAIICFKCTM-UHFFFAOYSA-N 0.000 claims description 3
- 229950008393 cariporide Drugs 0.000 claims description 3
- 150000002357 guanidines Chemical class 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006313 (C5-C8) alkyl group Chemical group 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 208000017194 Affective disease Diseases 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000005024 alkenyl aryl group Chemical group 0.000 claims description 2
- FZOCFRPFPKJHHP-UHFFFAOYSA-N benzyl n-(diaminomethylidene)carbamate Chemical class NC(N)=NC(=O)OCC1=CC=CC=C1 FZOCFRPFPKJHHP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical group COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- WBCXYMNAMCHKSU-UHFFFAOYSA-N n-(diaminomethylidene)-1h-indene-1-carboxamide Chemical class C1=CC=C2C(C(=O)NC(=N)N)C=CC2=C1 WBCXYMNAMCHKSU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000005413 thiopyridyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 110
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims 104
- 150000003839 salts Chemical class 0.000 claims 55
- 150000003254 radicals Chemical class 0.000 claims 25
- 239000011593 sulfur Substances 0.000 claims 25
- 125000000623 heterocyclic group Chemical group 0.000 claims 15
- 125000002947 alkylene group Chemical group 0.000 claims 11
- 150000001721 carbon Chemical group 0.000 claims 11
- 125000005842 heteroatom Chemical group 0.000 claims 8
- 239000002253 acid Substances 0.000 claims 7
- 150000001409 amidines Chemical class 0.000 claims 7
- 125000003277 amino group Chemical group 0.000 claims 7
- 125000001153 fluoro group Chemical group F* 0.000 claims 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 7
- 125000000304 alkynyl group Chemical group 0.000 claims 6
- 239000011737 fluorine Substances 0.000 claims 6
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 claims 6
- 125000005493 quinolyl group Chemical group 0.000 claims 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims 5
- 125000003107 substituted aryl group Chemical group 0.000 claims 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims 4
- 125000003435 aroyl group Chemical group 0.000 claims 4
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims 3
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims 3
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- 125000001931 aliphatic group Chemical group 0.000 claims 3
- 125000004429 atom Chemical group 0.000 claims 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 3
- 229920006395 saturated elastomer Polymers 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims 2
- 125000002723 alicyclic group Chemical group 0.000 claims 2
- 150000005840 aryl radicals Chemical class 0.000 claims 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N benzene-dicarboxylic acid Natural products OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 claims 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims 2
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims 2
- 125000004193 piperazinyl group Chemical group 0.000 claims 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 2
- 125000006664 (C1-C3) perfluoroalkyl group Chemical group 0.000 claims 1
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 1
- 208000027465 Psychotic Affective disease Diseases 0.000 claims 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000005025 alkynylaryl group Chemical group 0.000 claims 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 244000309464 bull Species 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 229930016911 cinnamic acid Natural products 0.000 claims 1
- 235000013985 cinnamic acid Nutrition 0.000 claims 1
- 150000001851 cinnamic acid derivatives Chemical class 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 claims 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 claims 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 claims 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 1
- 239000002934 diuretic Substances 0.000 claims 1
- 229940030606 diuretics Drugs 0.000 claims 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- XEHVFKKSDRMODV-UHFFFAOYSA-N ethynyl Chemical group C#[C] XEHVFKKSDRMODV-UHFFFAOYSA-N 0.000 claims 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 claims 1
- 125000004438 haloalkoxy group Chemical group 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- QAKJXJZBXCVFLX-UHFFFAOYSA-N n-(diaminomethylidene)-1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N=C(N)N)=CC2=C1 QAKJXJZBXCVFLX-UHFFFAOYSA-N 0.000 claims 1
- NGGXACLSAZXJGM-UHFFFAOYSA-N n-(diaminomethylidene)acetamide Chemical class CC(=O)N=C(N)N NGGXACLSAZXJGM-UHFFFAOYSA-N 0.000 claims 1
- APOPAXUENTVHHC-UHFFFAOYSA-N n-(diaminomethylidene)naphthalene-1-carboxamide Chemical class C1=CC=C2C(C(=O)NC(=N)N)=CC=CC2=C1 APOPAXUENTVHHC-UHFFFAOYSA-N 0.000 claims 1
- OECMIBNCPUMKFU-UHFFFAOYSA-N n-(diaminomethylidene)naphthalene-2-carboxamide Chemical class C1=CC=CC2=CC(C(=O)N=C(N)N)=CC=C21 OECMIBNCPUMKFU-UHFFFAOYSA-N 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 1
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- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
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- 125000005942 tetrahydropyridyl group Chemical group 0.000 claims 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
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- 239000011734 sodium Substances 0.000 description 5
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- 230000001537 neural effect Effects 0.000 description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
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- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 2
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- FNDLQABGYJQJPH-UHFFFAOYSA-N n-(diaminomethylidene)-3-methylsulfonyl-4-propan-2-ylbenzamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.CC(C)C1=CC=C(C(=O)N=C(N)N)C=C1S(C)(=O)=O FNDLQABGYJQJPH-UHFFFAOYSA-N 0.000 description 2
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical class O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 229910020587 CmF2m+1 Inorganic materials 0.000 description 1
- 206010058558 Hypoperfusion Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
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- 239000013543 active substance Substances 0.000 description 1
- 125000006193 alkinyl group Chemical group 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000001964 calcium overload Effects 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000003790 chinazolinyl group Chemical group 0.000 description 1
- 125000003787 chinoxalinyl group Chemical group 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000002566 clonic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000012105 intracellular pH reduction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
Definitions
- the invention describes the use of inhibitors of the cellular sodium-hydrogen exchanger for the manufacture of a drug for therapy and Prophylaxis of diseases and disorders caused by over - excitability of the Central nervous system are triggered, especially for the treatment of Diseases of the epiletica Formennikes, centrally triggered clonic and tonic spasms, anxiety disorders and psychosis.
- NHE sodium / hydrogen exchanger
- the mechanism of action of the NHE inhibitors is that they amplify the Sodium ion influx, which occurs in poorly blooded tissues by a Activation of NHE due to intracellular acidification occurs, diminishing. This delays the situation of sodium overloading the tissue. Since in the Hersgewebe sodium and calcium ion transport coupled with each other are the life-threatening calcium overload of the heart cells prevented.
- NHE inhibitors in addition to the protective effects, which only come to fruition under conditions of lack of circulation, too still direct therapeutically utilizable effects against diseases and Disorders of the CNS have independent of deficient blood states are and occur in normal, non-ischemic conditions.
- non-ischemic phenomena that have recently been reported NHE inhibitors can be made available to a treatment
- diseases and disorders that are caused by over-excitability caused by neurons of the central nervous system.
- On such Diseases and disorders act by inhibiting NHE inhibitors Hyperactivity of CNS neurons.
- Neuronal hyperactivity is not only seen in epilepsy. Also at other centrally triggered dysfunctions as in various psychoses neuronal hyperactivity is suspected as the cause in various brain areas. Since the described principle of inhibition of NHE neuronal Hyperactivity regardless of the trigger or can dampen disease is suitable It is not only for the treatment of epilepsy, but also for the treatment of mood disorders and anxiety disorders. The resulting Indications thus include the treatment of epilepsy and affective Psychosis and anxiety disorders.
- the antiepileptic and antipsychotic NHE inhibitors used alone be applied.
- the unique mechanism of action of NHE inhibitors but also makes it possible to combine NHE inhibitors with other active substances, which is based on another mechanism of action. So, for example Combinations of NHE inhibitors with other antiepileptic drugs Substances or antipsychotic agents, or carbonic anhydrase inhibitors (eg. As acetazolamide) allow favorable treatment regimens and treatment successes, the can not be achieved with the individual components of the combination.
- NHE inhibitors with their antiepileptic and antipsychotic therapeutic potential inhibit epileptiform discharges in the model of CA3 neurons in hippocampal tissue slices.
- Over-excitability of neurons (hyperexcitability) in the form of so-called epileptiform discharges was triggered by the action of bicuculline, caffeine or low magnesium concentrations.
- HOE 642, a blocker of the Na /H Isoform1 showed a pronounced inhibition of the excitatory effect of these substances caused epileptiform discharges.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742096 | 1997-09-24 | ||
| DE19742096A DE19742096A1 (de) | 1997-09-24 | 1997-09-24 | Die Verwendung eines Inhibitors des Na·+·/H·+·-Austauschers zur Herstellung eines Medikaments zur Behandlung oder Prophylaxe von Erkrankungen des Zentralnervensystems |
| DE1997150498 DE19750498A1 (de) | 1997-11-14 | 1997-11-14 | Die Verwendung eines Inhibitors des Na+/H+-Austauschers zur Herstellung eines Medikaments zur Behandlung oder Prophylaxe von Erkrankungen des Zentralnervensystems |
| DE19750498 | 1997-11-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0909559A2 true EP0909559A2 (de) | 1999-04-21 |
Family
ID=26040251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98117765A Withdrawn EP0909559A2 (de) | 1997-09-24 | 1998-09-18 | Die Verwendung eines Na+/H+-Austauschers zur Herstellung eines Medikaments zur Behandlung oder Propphylaxe von Erkrankungen des Zentralnervensystems |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US20040097544A1 (cs) |
| EP (1) | EP0909559A2 (cs) |
| JP (1) | JPH11158082A (cs) |
| KR (1) | KR19990030008A (cs) |
| CN (1) | CN1212149A (cs) |
| AR (1) | AR015724A1 (cs) |
| AU (1) | AU750355B2 (cs) |
| BR (1) | BR9803597A (cs) |
| CA (1) | CA2247733A1 (cs) |
| CZ (1) | CZ304698A3 (cs) |
| HR (1) | HRP980521A2 (cs) |
| HU (1) | HUP9802142A2 (cs) |
| IL (1) | IL126276A0 (cs) |
| NO (1) | NO984430L (cs) |
| NZ (1) | NZ332004A (cs) |
| SK (1) | SK130398A3 (cs) |
| TR (1) | TR199801887A2 (cs) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5030587B2 (ja) * | 2003-06-26 | 2012-09-19 | バイオトロン・リミテッド | 抗ウイルスアシルグアニジン化合物および方法 |
| CN102870764A (zh) * | 2011-07-13 | 2013-01-16 | 刘斌 | 一种新型灌注保存液 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3929582A1 (de) * | 1989-09-06 | 1991-03-07 | Hoechst Ag | Benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament sowie sie enthaltendes medikament |
| EP0589336B1 (de) * | 1992-09-22 | 1997-01-08 | Hoechst Aktiengesellschaft | Benzoylguanidine, Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Antiarrhythmika |
| DE4318756A1 (de) * | 1993-06-05 | 1994-12-08 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE4325822A1 (de) * | 1993-07-31 | 1995-02-02 | Hoechst Ag | Substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
| DE19531138A1 (de) * | 1995-08-24 | 1997-02-27 | Merck Patent Gmbh | Alkenyl-benzoylguanidin-Derivate |
| US5811244A (en) * | 1996-09-18 | 1998-09-22 | The Jackson Laboratory | In vitro method for identifying a clinical disorder associated with Nhe1 mutation |
-
1998
- 1998-09-17 IL IL12627698A patent/IL126276A0/xx unknown
- 1998-09-18 EP EP98117765A patent/EP0909559A2/de not_active Withdrawn
- 1998-09-22 TR TR1998/01887A patent/TR199801887A2/xx unknown
- 1998-09-22 JP JP10267583A patent/JPH11158082A/ja not_active Withdrawn
- 1998-09-22 KR KR1019980039151A patent/KR19990030008A/ko not_active Withdrawn
- 1998-09-22 CZ CZ983046A patent/CZ304698A3/cs unknown
- 1998-09-22 SK SK1303-98A patent/SK130398A3/sk unknown
- 1998-09-22 NZ NZ332004A patent/NZ332004A/en unknown
- 1998-09-22 AR ARP980104744A patent/AR015724A1/es unknown
- 1998-09-22 CA CA002247733A patent/CA2247733A1/en not_active Abandoned
- 1998-09-23 HR HR19750498.1A patent/HRP980521A2/hr not_active Application Discontinuation
- 1998-09-23 AU AU86157/98A patent/AU750355B2/en not_active Ceased
- 1998-09-23 BR BR9803597A patent/BR9803597A/pt not_active IP Right Cessation
- 1998-09-23 HU HU9802142A patent/HUP9802142A2/hu unknown
- 1998-09-23 CN CN98119693A patent/CN1212149A/zh active Pending
- 1998-09-23 NO NO984430A patent/NO984430L/no unknown
-
2003
- 2003-04-28 US US10/424,107 patent/US20040097544A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| IL126276A0 (en) | 1999-05-09 |
| AU750355B2 (en) | 2002-07-18 |
| NO984430D0 (no) | 1998-09-23 |
| AR015724A1 (es) | 2001-05-16 |
| JPH11158082A (ja) | 1999-06-15 |
| NO984430L (no) | 1999-03-25 |
| KR19990030008A (ko) | 1999-04-26 |
| TR199801887A2 (xx) | 1999-04-21 |
| BR9803597A (pt) | 2000-03-21 |
| CA2247733A1 (en) | 1999-03-24 |
| SK130398A3 (en) | 1999-05-07 |
| HU9802142D0 (en) | 1998-11-30 |
| HRP980521A2 (en) | 1999-06-30 |
| US20040097544A1 (en) | 2004-05-20 |
| HUP9802142A2 (hu) | 1999-04-28 |
| CN1212149A (zh) | 1999-03-31 |
| NZ332004A (en) | 2001-04-27 |
| AU8615798A (en) | 1999-04-15 |
| CZ304698A3 (cs) | 1999-04-14 |
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